{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:15:58Z","timestamp":1787026558871,"version":"build-2736575974"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Gastric cancer (GC) remains a leading cause of global cancer mortality, characterized by profound heterogeneity. While immune checkpoint blockade (ICB) has emerged as a promising strategy, pervasive resistance frequently limits its clinical efficacy. Elucidating the mechanisms driving this resistance and identifying predictive biomarkers remain critical challenges for achieving precision oncology in GC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We constructed a spatial multi-omic atlas by integrating scRNA-seq from GC patients with public spatial transcriptomics (ST) data. Computational deconvolution of independent immunotherapy cohorts was performed to pinpoint specific macrophage and fibroblast subsets linked to ICB efficacy. Intercellular immunosuppressive signaling and spatial proximity were characterized via cell-cell communication and ST analysis. We validated the biological significance of this crosstalk using non-contact co-culture systems and mIHC analysis of an independent clinical cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We constructed a spatially resolved multi-omic atlas by integrating scRNA-seq from 131,027 cells with spatial transcriptomics. Deconvolution of immunotherapy cohorts identified the synchronous enrichment of SPP1+macrophages and MFAP5+fibroblasts in tumors with poor ICB efficacy. Spatial analysis quantified a significant co-localization between CSF1-producing malignant cells and SPP1\n                      <jats:sup>+<\/jats:sup>\n                      macrophages. Experimentally, malignant cell-derived CSF1 induced SPP1+ macrophage polarization, triggering the synergistic upregulation of\n                      <jats:italic>IL-10<\/jats:italic>\n                      and\n                      <jats:italic>TGF-\u03b21<\/jats:italic>\n                      . This crosstalk significantly enhanced GC cell colony formation and invasive potential, as confirmed by secretome profiling and functional assays. Finally, mIHC staining validated the co-localization of CSF1+malignant cells and SPP1+macrophages\n                      <jats:italic>in situ<\/jats:italic>\n                      within clinical tumor tissues.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study identifies a spatially organized niche involving CSF1+malignant cells and SPP1+ macrophages as a key driver of ICB resistance in GC. By defining the CSF1-mediated crosstalk between these two cell types, these findings highlight promising therapeutic targets to enhance the efficacy of immunotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1817573","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T05:37:15Z","timestamp":1781588235000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["The CSF1+ tumor cell\u2013SPP1+ macrophage axis drives gastric cancer progression and immunotherapy resistance"],"prefix":"10.3389","volume":"17","author":[{"given":"Heng","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Gastrointestinal Surgery, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science","place":["Xiangyang, Hubei, 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